(1) Field of the Invention
This invention relates to benzo[ij]quinolizine-2-carboxylic acid derivatives. More particularly, it relates to 9-halogeno-5-alkyl-8-(unsubstituted to trisubstituted piperazinyl) benzo[ij]quinolizine-2-carboxylic acid derivatives having good absorbability from the digestive tract into the circulating blood and exhibiting long-lasting antibacterial activity.
(2) Description of the Prior Art
In the field of synthetic antibacterial agents, typical examples of well-known compounds having a halogen substituent and containing a pyridonecarboxylic acid structure include 1-ethyl-6-fluoro-1, 4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (hereinafter referred to as norfloxacin; Japanese Patent Publication No. 34,144/'80), 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2, 3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (hereinafter referred to as ofloxacin; Japanese Patent Laid-Open Nos. 46,986/'82 and 34,968/'85), 9-fluoro-6,7-dihydro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid (hereinafter referred to as OPC-7241; Japanese Patent Laid-Open No. 76,875/'80), 9-fluoro-6,7-dihydro-1,7-dioxo-5-methyl-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid (hereinafter referred to as Compound .alpha.; Japanese Patent Laid-Open No. 127,099/'76) and the like. (Ofloxacin) ##STR2##
However, it was reported by Murayama et al. (CHEMOTHERAPY, Vol. 29, Supplement No. 4, p. 98, 1981) that, when norfloxacin was administered orally to fasted animals (e.g., mice) in a dose of 50 mg/kg, its degree of absorption into the serum after 30 minutes was expressed by an average peak value of 1.+-.0.6 .mu.g/ml. Moreover, it was discussed by Goto et al. (CHEMOTHERAPY, Vol. 32, Supplement No. 1, p. 22, 1984) that norfloxacin exhibited excellent antibacterial activity when evaluated by in vitro tests with Gram-negative and Gram-positive bacteria, but it was somewhat disadvantageous in enteral absorbability.
Thus, recent studies of synthetic antibacterial agents containing a pyridonecarboxylic acid structure have come to focus attention on their bioavailability (the degree of biological utilizability) in case of oral administration, rather than on their relative superiority in antibacterial activity, provided that they have at least a certain level of activity. In the course of such studies, ofloxacin and OPC-7241 were developed. It was reported by Goto et al. (CHEMOTHERAPY, Vol. 32, Supplement No. 1, p. 22, 1984) that, when ofloxacin was administered orally to fasted mice in a dose of 1 mg/mouse (equivalent to 50 mg/kg body weight), its serum concentration reached 10 .mu.g/ml after 30 minutes, indicating an increase in enteral absorbability over norfloxacin. From the viewpoint of bioavailability, however, enternal absorbability still leaves room for improvement. In addition, it was also described in the same report that, 2 hours after administration, its residual concentration in the serum decreased to 1.5 .mu.g/ml. This indicates the necessity of developing a technique for prolonging the duration of action of such drugs.
As for OPC-7241, it was presented in the lecture given at the Fifth Medicinal Chemistry Symposium (Kyoto; Dec. 9-10, 1984) on the subject of "Structures and Antibacterial Activities of Pyrido[1,2,3-de]-1, 4-benzoxazine-6-carboxylic acid-related Compounds" that its enteral absorbability was almost equal to that of ofloxacin. Accordingly, it may be expected that OPC-7241 involves the same problems as described in connection with ofloxacin.
On the other hand, Compound .alpha. has only been reported to be useful as an intermediate material for the preparation of 9-fluoro-6, 7-dihydro-7-hydroxy-5-methyl-1-oxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid (Japanese Patent Laid-Open No. 127,099/'76), and no detailed report on its antibacterial activity has been published. When the present inventors conducted a confirmatory experiment on the antibacterial activity of Compound .alpha., it was found that its efficacy against Gram-positive bacteria was low and, moreover, it was utterly ineffective against Gram-negative bacteria (such as Pseudomonas aeruginosa, Serratia marcescens and the like) to which great importance has recently been attached especially in the field of bacterial infection.